In general, the invention relates to methods and compounds that decrease secretion of proteins encoded by ARE-mRNAs, such as Tumor Necrosis Factor (TNFα), or that modulate regulation of ARE-mRNAs.
ARE-mRNAs are mRNA molecules that contain an adenylate uridylate (AU)-rich element. AREs are usually found in the 3′ untranslated region (3′ UTR) of mRNAs rather than in the coding region. ARE regulatory regions modulate the rate of mRNA degradation and the rate of translation. A database of human mRNAs containing an ARE consensus sequence was recently reported (Bakheet et al., Nucleic Acids Research 29:246-254, 2001).
One such ARE-mRNA encodes TNFα, which is a pleiotropic cytokine produced predominantly by activated monocytes/macrophages. TNFα is a primary mediator of numerous immune functions, including hemorrhagic cytotoxicity, inflammation, and regulation of antiviral and immune proliferative and activation responses. As a central member of the cytokine network, TNFα has been implicated in a variety of disease states, including cachexia, endotoxic (septic) shock, acute respiratory distress syndrome, and a number of necrotic, proliferative, and autoimmune diseases.
TNFα exhibits a potent cytolytic and cytostatic activity towards a variety of cells, including tumor cell lines and virally infected cells. For example, TNFα is a potent mediator of monocyte/macrophage migration, activation, and differentiation. In addition, TNFα stimulates activated T-cells and B-cells and enhances neutrophil chemotaxis and phagocytic activity. Endothelial cells are also primary targets of TNFα activity; for example, TNFα induces the release of IL-1 from endothelial cells and promotes endothelial cell procoagulant activity and neutrophil adhesion, which are involved in local inflammatory responses. TNFα also stimulates fibroblast migration, proliferation, and cytokine production.